Abstract
Background
To investigate the association between absolute lymphocyte count (ALC) nadir and survival outcomes in esophageal squamous cell carcinoma (ESCC) patients who received definitive chemoradiotherapy (CRT) combined with anti-PD-1 immunotherapy, as well as to explore clinical characteristics and dosimetric parameters that affect ALC nadir during CRT.
Patients and Methods
Patients with ESCC (n = 602) who underwent definitive CRT were analyzed, of whom 166 received combined anti-PD-1 immunotherapy and CRT. Changes in ALC and survival were compared between patients with and without immunotherapy. Propensity score matching (PSM) was performed to minimize the effects of confounding factors. Low ALC was defined as nadir of <0.33 × 103 cells/μL during CRT (top tertile). Univariate and multivariate logistic regression were used to identify predictors of low ALC nadir.
Results
Patients with immunotherapy had significantly higher ALC in the first 3 weeks during CRT and higher ALC nadir than those without. Overall survival was more favorable in patients with immunotherapy both before and after PSM. After a median follow-up of 12.1 months, patients with low ALC during CRT had a worse progression-free survival (PFS) (P = .026). In multivariate analysis, low ALC remained a significant prognostic factor for PFS. Planning target volume (PTV) and heart V5 were revealed to be independent predictors of low ALC.
Conclusions
The addition of anti-PD-1 immunotherapy to definitive CRT could mitigate the decline of ALC during radiotherapy and might prolong survival. Low ALC nadir was correlated to worse PFS, larger PTV, and higher heart V5 in patients receiving combined immunotherapy and CRT.
Keywords: immunotherapy, definitive chemoradiotherapy, esophageal squamous cell carcinoma, absolute lymphocyte count, survival
This study investigated the predictive role of lymphopenia in patients with esophageal squamous cell carcinoma who received definitive chemoradiotherapy combined with anti-PD-1 immunotherapy.
Implications for Practice.
The purpose of this study was to investigate the predictive role of lymphopenia in esophageal squamous cell carcinoma patients who received definitive chemoradiotherapy (CRT) combined with anti-PD-1 immunotherapy, as well as the clinical factors and dosimetric parameters that impact lymphopenia during CRT. Based on a cohort of 602 patients, our results indicated that the addition of immunotherapy to definitive CRT could mitigate the decline of absolute lymphocyte count (ALC) during radiotherapy and might prolong survival. More importantly, low ALC nadir was correlated to worse progression-free survival, larger planning target volumes, and higher heart V5 in patients receiving combined immunotherapy and CRT.
Introduction
Esophageal cancer (EC) is the seventh most prevalent malignant tumor and the sixth leading cause of death worldwide.1 Esophageal squamous cell cancer (ESCC) is the predominant histological subtype in China. Definitive chemoradiotherapy (CRT) is the standard treatment for patients with locally advanced unresectable esophageal cancer.2 In recent years, immune checkpoint inhibitors (ICIs) have been shown to improve survival outcomes in advanced EC based on a series of high-quality clinical trials.3-6 Immunotherapy in combination with conventional treatment strategies is being investigated to boost efficacy even further.
Radiotherapy can kill tumor cells directly, promoting the release of tumor antigens and thus triggering the immune response and enhancing systemic immune recognition.7 Combining radiation and immunotherapy have been demonstrated to enhance the antitumor efficacy in solid tumors.8 Furthermore, programmed death receptor 1 (PD-1) inhibitors in combination with CRT have indicated acceptable safety and promising efficacy in treating EC.9-11 Of note, the mechanism of ICIs is strictly dependent on lymphocytes. Therapeutic antibodies bind to molecules on the surface of T cells, such as PD-1 and cytotoxic T lymphocyte antigen 4 (CTLA-4), or PD-1 ligand 1 (PD-L1) expressed on tumor cells.12 Nevertheless, lymphocytes are extremely radiosensitive and lymphopenia is very common during radiotherapy. Therefore, radiation-induced lymphopenia may diminish the antitumor effects of immunotherapy. The interaction between radiotherapy and immunotherapy has yet to be fully elucidated.
Several studies have shown an association between lymphopenia and poor prognosis in EC patients undergoing traditional CRT, especially grade 4 lymphopenia.13-18 However, few studies have investigated the clinical implications of lymphopenia in the immunotherapy era for EC patients. Moreover, differences in treatment-related lymphopenia between patients receiving CRT alone or combined with immunotherapy remain unknown. Additionally, the possible risk factors associated with lymphopenia have not been studied in EC patients treated with a combination of ICIs and CRT. Therefore, this study aimed to investigate the predictive role of lymphopenia in ESCC patients who received definitive CRT combined with anti-PD-1 immunotherapy, as well as the clinical factors and dosimetric parameters that impact lymphopenia during CRT.
Materials and Methods
Patient Selection
Medical records of ESCC patients who received definitive CRT between February 2009 and March 2021 at our institution were retrospectively reviewed. Patients who met the following criteria were included in this analysis: (1) pathologically confirmed as stage II–IVa ESCC according to the eighth TNM staging system defined by the American Joint Committee on Cancer; (2) received definitive CRT combined with or without anti-PD-1 immunotherapy of a total radiation dose ≥40 Gy, with accessible dosimetric parameters; and (3) had at least 3 weekly blood tests results available during CRT and 1 month after CRT. Patients with concomitant malignant tumor or who received anti-PD-1 immunotherapy only after the completion of CRT were excluded. The Institutional Review Board of our center approved this study. Owing to the retrospective study design, informed consent was waived.
Physical examination, standard blood tests, esophagogastroduodenoscopy (EGD) with endoscopic ultrasound and biopsies, X-ray esophagography, chest/abdominal computed tomography (CT), and/or positron emission tomography (PET) were completed in all patients prior to treatment.
Treatment and Follow-Up
A fraction of patients received 1-4 cycles of induction chemotherapy before radiotherapy. All patients received chemotherapy concurrently with radiotherapy using intensity-modulated radiotherapy. The total radiation dose was 40-68 Gy in 20-33 fractions. The anti-PD-1 immunotherapy was combined with induction chemotherapy and/or concurrent CRT. After CRT, most patients continued to receive maintenance immunotherapy every 2 or 3 weeks for 1 year.
Patients were followed up 1 and 3 months after CRT, then every 3 months during the first 2 years, every 6 months for the next 3 years, and then annually. Blood tests, chest and abdominal CT, EGD, and/or PET-CT were performed during follow-up. Disease progression was defined as recurrences in esophagus or regional lymph nodes, or metastases in non-regional lymph nodes or distant organs.
Data Collection
Absolute lymphocyte count (ALC) values were obtained at baseline, during induction chemotherapy and concurrent CRT weekly, and 1 and 3 months after the completion of CRT. Low ALC was defined as ALC nadir <0.33 × 103 cells/μL during CRT, which was the highest tertile of all patients receiving combined anti-PD-1 immunotherapy and CRT in the study. A variety of dosimetric parameters for the lung and heart were extracted for analysis, and data were described as mean doses and the percentage of the total lung or heart volume receiving more than x Gy (Vx). PD-L1 status of pretreatment tumor biopsies was determined by immunohistochemical (IHC) staining using the 22C3 assay (Dako North America, CA). PD-L1 positivity was defined as a combined positive score (CPS) of ≥10, and CPS is the number of PD-L1 positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of tumor cells ×100.
Propensity Score Matching
To minimize the impact of potential confounding factors on lymphocyte and survival outcomes, we performed propensity score matching (PSM) analysis using a 1:2 ratio nearest neighbor algorithm between patients with or without immunotherapy. Sex, performance status, weight loss, histologic grade, induction chemotherapy, and radiation dose were included for PSM.
Statistical Analysis
Patient baseline characteristics were summarized using descriptive statistics. Hematologic variables were divided into 2 groups by median value and compared through Mann-Whitney U tests, whereas dosimetric parameters were analyzed as continuous variables. Chi-square tests were used for proportional comparison. Progression-free survival (PFS) was calculated from the time of pathology-confirmed diagnosis until the time when the disease progressed or the patient was censored at the most recent follow-up. Survival analyses were performed using log-rank test of the Kaplan-Meier survival curves. Cox proportional hazards regression was used when assessing survival in univariate and multivariate analyses. To assess the risk factors for low ALC, we performed a univariate analysis followed by a multivariate logistic regression. Variables with P ≤ .15 in univariate analysis were included in a multivariate model, which was then optimized by Backward-stepwise selection. Multicollinearity between dosimetric parameters was assessed with Spearman rank correlations before multivariate analysis. SPSS version 20.0 (IBM Corp., Armonk, NY, USA) was used for all statistical analyses, while R software version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria) was used for PSM. P values < .05 were considered to be statistically significant.
Results
Patient and Treatment Characteristics
A total of 602 patients who met the inclusion criteria were included in this analysis, of whom 166 (27.6%) received anti-PD-1 immunotherapy and 436 (72.4%) did not. Table 1 lists the baseline and treatment characteristics of all patients. The median age at diagnosis was 59 years (range, 27-82 years), and median tumor length was 5.0 cm (range, 1.0-16.9 cm). Most patients (60.8%) had a tumor located in the middle or distal esophagus. As for clinical TNM stage, only 54 (9%) patients were stage II, 173 (28.7%) were stage III, and 375 (62.3%) were stage IVa. A total of 391 patients (65.0%) received induction chemotherapy prior to concurrent CRT. The most commonly used concurrent chemotherapy regimen was taxane/platinum doublet (53.7%).
Table 1.
Patient characteristics.
| Characteristic | Total (n = 602), % | With ICI (n = 166), % | Without ICI (n = 436), % |
|---|---|---|---|
| Age (years) | |||
| Median (range) | 59 (27-82) | 61 (46-77) | 59 (27-82) |
| Sex | |||
| Male | 460 (76.4) | 141 (84.9) | 319 (73.2) |
| Female | 142 (23.6) | 25 (15.1) | 117 (26.8) |
| Smoking history | |||
| Yes | 386 (64.1) | 95 (57.2) | 291 (66.7) |
| No | 216 (35.9) | 71 (42.8) | 145 (33.3) |
| Alcohol history | |||
| Yes | 283 (47.0) | 87 (52.4) | 196 (45.0) |
| No | 319 (53.0) | 79 (47.6) | 240 (55.0) |
| ECOG-PS | |||
| 0 | 429 (71.3) | 139 (83.7) | 290 (66.5) |
| 1-2 | 173 (28.7) | 27 (16.3) | 146 (33.5) |
| BMI (kg/m²) | |||
| ≤18.5 | 69 (11.5) | 17 (10.2) | 52 (11.9) |
| >18.5 | 533 (88.5) | 149 (89.8) | 384 (88.1) |
| Weight loss | |||
| <10% | 496 (82.4) | 151 (91.0) | 345 (79.1) |
| ≥10% | 106 (17.2) | 15 (9.0) | 91 (20.9) |
| Histologic grade | |||
| Gx/1/2 | 438(72.8) | 98 (59.0) | 340 (78.0) |
| G3 | 164 (27.2) | 68 (41.0) | 96 (22.0) |
| Tumor location | |||
| Upper | 236 (39.2) | 63 (38.0) | 173 (39.7) |
| Middle | 277 (46.0) | 72 (43.4) | 205 (47.0) |
| Distal | 89 (14.8) | 31 (18.7) | 58 (13.3) |
| Primary tumor length | |||
| ≤5 cm | 263 (43.7) | 80 (48.2) | 183 (42.0) |
| >5 cm | 339 (56.3) | 86 (51.8) | 253 (58.0) |
| Clinical TNM stage | |||
| II | 54 (9.0) | 10 (6.0) | 44 (10.1) |
| III | 173 (28.7) | 54 (32.5) | 119 (27.3) |
| Iva | 375 (62.3) | 102 (61.4) | 273 (62.6) |
| Induction chemotherapy | |||
| Yes | 391 (65.0) | 119 (71.7) | 272 (62.4) |
| No | 211 (35.0) | 47 (28.3) | 164 (37.6) |
| Concurrent chemotherapy regimen | |||
| Platinum/taxane | 323 (53.7) | 94 (56.6) | 229 (52.5) |
| Platinum/fluorouracil | 102 (16.9) | 17 (10.2) | 85 (19.5) |
| Othera | 177 (29.4) | 55 (33.1) | 122 (28.0) |
| Radiation dose (Gy) | |||
| ≤56 | 384 (63.8) | 95 (57.2) | 147 (33.7) |
| >56 | 218 (36.2) | 71 (42.8) | 289 (66.3) |
| Pre-CRT ALC (109/L) | |||
| Median (IQR) | 1.79 (1.40-2.25) | 1.74 (1.41-2.24) | 1.80 (1.40-2.29) |
| Pre-CRT neutrophil (109/L) | |||
| Median (IQR) | 4.80 (3.60-6.22) | 5.04 (3.95-6.31) | 4.70 (3.50-6.20) |
| Pre-CRT monocyte (109/L) | |||
| Median (IQR) | 0.50 (0.40-0.70) | 0.49 (0.41-0.62) | 0.50 (0.40-0.70) |
| Pre-CRT platelet (109/L) | |||
| Median (IQR) | 254 (206-315) | 279 (231-334) | 246 (196-301) |
| Pre-CRT hemoglobin (g/L) | |||
| Median (IQR) | 134.0 (124.0-144.0) | 138.0 (129.8-148.0) | 133.0 (123.0-142.0) |
| Pre-CRT albumin (g/L) | |||
| Median (IQR) | 41.6 (39.2-43.8) | 42.8 (40.9-44.9) | 41.1 (38.2-43.3) |
| Pre-CRT LDH (U/L) | |||
| Median (IQR) | 168.8 (146.7-190.4) | 171.9 (153.2-194.1) | 167.6 (145.6-189.9) |
aSingle agent chemotherapy (taxane, platinum, fluorouracil or other).
Abbreviations: ALC, absolute lymphocyte count; BMI, body mass index; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; ICI, Immune checkpoint inhibitor; IQR, interquartile range; LDH, lactate dehydrogenase
For the 166 patients who received combined anti-PD-1 immunotherapy and CRT, the most commonly used type of anti-PD-1 inhibitor was toripalimab (72.9%), followed by sintilimab (14.5%). Of them, 119 patients (71.7%) received induction chemotherapy plus anti-PD-1 immunotherapy prior to radiotherapy. A total of 128 patients (77.1%) underwent anti-PD-1 immunotherapy concurrently with radiotherapy, and the majority of patients (85.5%) continued to receive maintenance immunotherapy after CRT.
ALC During CRT
Patients were sorted into 2 groups (ICI group vs. non-ICI group) according to whether they received anti-PD-1 immunotherapy. For patients receiving induction chemotherapy, ALC decline was not significant during induction chemotherapy in both groups, with median ALC values of 1.64, 1.79, 1.65, and 1.74 × 103 cells/μL in each cycle in the ICI group, and 1.70, 1.70, 1.70, and 1.52 × 103 cells/μL in the non-ICI group, respectively (Fig. 1A). Mann-Whitney U test indicated no statistical difference between the 2 groups.
Figure 1.
Distribution of absolute lymphocyte count (ALC) among patients treated with (n = 166) or without immune checkpoint inhibitors (ICIs) (n = 436) during the course of (A) induction chemotherapy (IC) and (B) chemoradiotherapy (CRT) before propensity score matching, and (C) ALC nadir during CRT between groups.
During CRT, ALC decreased significantly in both groups. The most rapid decreases happened in the first 2 weeks. It reached a nadir in the fourth week and then maintained at the plateau, and then returned to normal but remained lower than pre-treatment levels at 1 month after CRT. In the ICI group, the median ALC before CRT was 1.74 × 103 cells/μL, which reduced weekly to 1.17, 0.68, 0.47, 0.35, and 0.35 × 103 cells/μL (Fig. 1B). The median ALC in the non-ICI group was 1.80 × 103 cells/μL prior to CRT, which dropped weekly to 0.80, 0.50, 0.40, 0.30, and 0.30 × 103 cells/μL (Fig. 1B). The ALC values were significantly different between groups in the first 3 weeks (P < .001). In addition, the median ALC nadir during CRT was significantly higher in the ICI group (0.28 vs. 0.20 × 103 cells/μL, P < .001; Fig. 1C).
Regarding low ALC nadir (<0.33 × 103 cells/μL), 108 patients (65.1%) had low ALC during CRT in the ICI group, while the percentage (79.6%) was much higher in the non-ICI group (P < .001), suggesting that the addition of immunotherapy can mitigate the decline of ALC during CRT.
To minimize the impact of potential confounding factors on clinical results, we performed PSM between the 2 groups. After PSM, 137 patients treated with ICI were matched to 221 patients without ICI. The baseline clinical characteristics of the 2 groups were comparable, as reported in Supplementary Table S1. Likewise, patients with ICI had significantly higher ALC in the first 3 weeks during CRT and higher ALC nadir after PSM (P < .001; Supplementary Fig. S1).
Anti-PD-1 Immunotherapy Provides Better Survival
At the median follow-up time of 17.4 months (range, 1.1-108.8 months) for the entire cohort, 322 patients (53.5%) had died and 394 (65.4%) experienced disease progression. The ICI group had a significantly better overall survival (OS) compared with the non-ICI group (P = .004; Fig. 2A), with 2-year OS rates of 60.2% and 49.3%, respectively. However, there was no statistical difference in PFS between the 2 groups (Fig. 2B). After PSM, similar results were found: patients with ICI had significantly more favorable OS than did the non-ICI group (P = .001, Fig. 2C).
Figure 2.
Kaplan-Meier estimates of survival curves for (A and C) overall survival and (B and D) progression-free survival in patients treated with or without immune checkpoint inhibitors (ICIs) before and after propensity score matching (PSM).
Association Between ALC and Survival in ICI group
The median follow-up time for the ICI group of 166 patients was 12.1 months (range, 3.2-34.4 months), and 81 patients (48.8%) developed disease progression during this follow-up period. Considering the relatively short follow-up period in this cohort, we further examined the association between ALC nadir and PFS. Patients with low ALC had a substantially shorter PFS than those with high ALC (P = .026; median PFS: 13.5 vs. not reached; Fig. 3A), with corresponding 2-year PFS rates of 32.5% and 52.4%, respectively.
Figure 3.
Comparison of survival curves for patients with different absolute lymphocyte count (ALC) nadir and estimated risk of low ALC nadir during chemoradiotherapy (CRT). (A) Kaplan-Meier analysis for progression-free survival between patients with high ALC nadir and low ALC nadir. Model to represent the estimated risk of low ALC nadir as a function of (B) the planning target volume (PTV) and (C) heart V5 in patients treated with or without immune checkpoint inhibitors (ICIs). Shaded regions represent 95% point-wise confidence intervals.
Table 2 summarizes the prognostic factors for PFS in the ICI cohort. In univariate analysis, age, body mass index, weight loss proportion, alcohol history, tumor length, induction chemotherapy, radiation dose, and ALC nadir were related to PFS. Multivariate analysis revealed that age <59 years (HR, 1.744; 95% CI, 1.102-2.760; P = .018); weight loss proportion >10% (HR, 2.082; 95% CI, 1.119-3.876; P = .021); radiation dose ≤56 Gy (HR, 1.829; 95% CI, 1.121-2.982; P = .016); and low ALC nadir during CRT (HR, 1.756; 95% CI, 1.069-2.886; P = .026) were independent predictors of unfavorable PFS.
Table 2.
Univariate and multivariate analyses for progression-free survival (n = 166).
| Variable | Univariate | Multivariate | ||
|---|---|---|---|---|
| Hazard ratio (95% CI) | P-value | Hazard ratio (95% CI) | P-value | |
| Sex (male vs. female) | 0.927 (0.521-1.649) | .769 | ||
| Age (<59 vs. ≥59 years) | 1.869 (1.204-2.900) | .005 | 1.744 (1.102-2.760) | .018 |
| BMI (<18.5 vs. ≥18.5) | 0.583 (0.308-1.104) | .098 | ||
| ECOG-PS (0 vs. 1-2) | 1.560 (0.804-3.026) | .867 | ||
| Weight loss proportion (≥10% vs. <10%) | 2.342 (1.263-4.341) | .007 | 2.082 (1.119-3.876) | .021 |
| Smoking history (yes vs. no) | 0.838 (0.538-1.303) | .432 | ||
| Alcohol history (yes vs. no) | 0.679 (0.437-1.056) | .086 | ||
| Histologic grade (G1-2, X vs. G3) | 0.800 (0.517-1.240) | .318 | ||
| Tumor Length (≤5 vs. >5 cm) | 0.722 (0.466-1.121) | .146 | ||
| Tumor location (upper vs middle/distal) | 0.929 (0.592-1.459) | .749 | ||
| Clinical TNM stage (II/III vs. IVa) | 0.726 (0.457-1.153) | .175 | ||
| Induction chemotherapy (yes vs. no) | 0.700 (0.442-1.108) | .128 | ||
| Concurrent chemotherapy regimena (1 vs. 2/3) | 0.779 (0.503-1.205) | .779 | ||
| Radiation dose (≤56 vs. >56 Gy) | 2.160 (1.340-3.480) | .002 | 1.829 (1.121-2.982) | .016 |
| Pre-CRT ALC (≤1.7 vs. >1.7 × 109/L) | 0.958 (0.619-1.483) | .847 | ||
| Pre-CRT neutrophil (≤5.0 vs.. >5.0 × 109/L) | 0.863 (0.551-1.320) | .475 | ||
| Pre-CRT monocyte (≤0.5 vs. >0.5 × 109/L) | 1.027 (0.662-1.593) | .905 | ||
| Pre-CRT platelet (≤280 vs. >280 × 109/L) | 0.903 (0.584-1.398) | .648 | ||
| Pre-CRT albumin (≤43 vs. >43 g/L) | 1.045 (0.676-1.617) | .842 | ||
| Pre-CRT hemoglobin (≤138 vs. >138 g/L) | 1.108 (0.716-1.715) | .646 | ||
| Pre-CRT LDH (≤170 vs. >170 U/L) | 1.046 (0.676-1.619) | .841 | ||
| ALC nadir during CRT (low vs. high) | 1.736 (1.063-2.835) | .028 | 1.756 (1.069-2.886) | .026 |
aChemotherapy regimen: 1, platinum/taxane; 2, platinum/fluorouracil; and 3, other.
Abbreviations: ALC, absolute lymphocyte count; BMI, body mass index; CRT, chemoradiotherapy; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; LDH, lactate dehydrogenase.
Clinical and Dosimetric Factors Associated with ALC
Since low ALC is an independent risk factor for PFS, we further performed univariate and multivariate logistic regression analysis (Table 3) to identify the clinical factors related to ALC nadir during CRT. Although univariate analysis showed tumor location, tumor length, planning target value (PTV), and anti-PD-1 immunotherapy with induction chemotherapy to be determinants of ALC nadir, only PTV (OR, 1.002; 95% CI, 1.000-1.004; P = .041) and tumor location (OR, 0.476; 95% CI, 0.242-0.935; P = .031) were found as independent predictors in multivariate logistic regression.
Table 3.
Univariate and multivariate analyses for low ALC nadir during CRT (n = 166).
| Variable | Univariate | Multivariate without dosimetric parameters | Multivariate with dosimetric parameters | |||
|---|---|---|---|---|---|---|
| Odds ratio (95% CI) | P-value | Odds ratio (95% CI) | P-value | Odds ratio (95% CI) | P-value | |
| Clinical characteristics | ||||||
| Sex (male vs. female) | 1.906 (0.807−4.505) | .141 | ||||
| Age (<59 vs. ≥59) | 1.055 (0.555−2.004) | .871 | ||||
| BMI (<18.5 vs. ≥18.5) | 1.017 (0.356−2.908) | .974 | ||||
| ECOG-PS (0 vs. 1-2) | 0.918 (0.384−2.198) | .848 | ||||
| Weight loss proportion (<10% vs. ≥10%) | 0.436 (0.118−1.614) | .214 | ||||
| Smoking history (yes vs. no) | 1.634 (0.857−3.114) | .136 | ||||
| Alcohol history (yes vs, no) | 1.290 (0.681−2.445) | .435 | ||||
| Histologic grade (G1-2, X vs. G3) | 0.873 (0.457−1.668) | .681 | ||||
| Tumor length (>5 vs. ≤5 cm) | 2.130 (1.112−4.083) | .023 | ||||
| Tumor location (upper vs. middle/distal) | 0.459 (0.239−0.885) | .020 | 0.476 (0.242-0.935) | .031 | ||
| Clinical TNM stage (II/III vs. IVa) | 0.931 (0.484−1.791) | .831 | ||||
| Chemotherapy regimena (1 vs. 2/3) | 0.775 (0.409-1.469) | .435 | ||||
| Induction chemotherapy (yes vs. no) | 1.790 (0.894−3.582) | .100 | ||||
| Pre-CRT ALC (≤1.7 vs. >1.7 × 109/L) | 1.272 (0.669-2.418) | .463 | ||||
| Pre-CRT neutrophil (≤5.0 vs. >5.0 × 109/L) | 0.922 (0.545−1.955) | .922 | ||||
| Pre-CRT monocyte (≤0.5 vs. >0.5 × 109/L) | 1.005 (0.531−1.903) | .987 | ||||
| Pre-CRT platelet (≤280 vs. >280 × 109/L) | 1.428 (0.752−2.710) | .276 | ||||
| Pre-CRT albumin (≤43 vs. >43 g/L) | 1.332 (0.702−2.525) | .380 | ||||
| Pre-CRT hemoglobin (≤138 vs. >138 g/L) | 0.969 (0.512−1.834) | .922 | ||||
| Pre-CRT LDH (≤170 vs. >170 U/L) | 0.603 (0.317−1.147) | .123 | ||||
| Radiation dose (≤56 vs. >56 Gy) | 1.137 (0.598-2.165) | .695 | ||||
| PTV (per increase of 1 cc) | 1.002 (1.000−1.004) | .018 | 1.002 (1.000-1.004) | .041 | 1.002 (1.000-1.004) | .042 |
| Dosimetric parameters | ||||||
| MLD (per increase of 1 Gy) | 1.157 (1.029−1.301) | .015 | ||||
| Lung V5 (per increase of 1%) | 1.023 (1.004−1.042) | .008 | ||||
| Lung V10 (per increase of 1%) | 1.021 (0.994−1.047) | .125 | ||||
| Lung V20 (per increase of 1%) | 1.049 (0.998−1.102) | .060 | ||||
| Lung V30 (per increase of 1%) | 1.080 (1.004−1.161) | .038 | ||||
| MHD (per increase of 1 Gy) | 1.062 (1.027−1.099) | <.001 | ||||
| Heart V5 (per increase of 1%) | 1.019 (1.009−1.029) | <.001 | 1.018 (1.008-1.028) | .001 | ||
| Heart V10 (per increase of 1%) | 1.017 (1.007−1.027) | .001 | ||||
| Heart V20 (per increase of 1%) | 1.020 (1.008−1.032) | .001 | ||||
| Heart V30 (per increase of 1%) | 1.031 (1.011−1.052) | .002 | ||||
| Heart V40 (per increase of 1%) | 1.053 (1.013−1.095) | .010 | ||||
aChemotherapy regimen: 1, platinum/taxane; 2, platinum/fluorouracil; and 3, other.
Abbreviations: ALC, absolute lymphocyte count; BMI, body mass index; CRT, chemoradiotherapy; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; LDH, lactate dehydrogenase; MHD, mean heart dose; MLD, mean lung dose; PTV, planning target volume; Vx: percentage of the total lung or heart volume receiving more than x Gy
To further explore the impact of radiation on ALC, we added dosimetric factors to the analyses. Mean lung dose (MLD), mean heart dose (MHD), V5-30 of lung, and V5-40 of heart were found to be associated with ALC nadir. According to Spearman rank correlation analyses, there were strong correlations between V5, V10 of lung, and MLD, V10, V20, V30 of heart and MHD (γ > 0.800, P < .001, Supplementary Table S2). To avoid multicollinearity, we only added MLD, MHD, V20 of lung, and V5 of heart into the multivariate analysis. PTV (OR, 1.002; 95% CI, 1.000-1.004; P = .042) and V5 of heart (OR, 1.018; 95% CI, 1.008-1.028; P = .001) were independently associated with ALC nadir, whereas tumor location was no longer significant. As shown in Fig. 3B, 3C, larger PTV and higher heart V5 were associated with increasing probability of low ALC nadir in patients with or without ICI based on the logistic regression model. Additionally, this model more objectively illustrated that the addition of ICI reduces the risk of ALC decline during CRT.
PD-L1 Expression and Survival Outcomes
PD-L1 status was available for 50 (30.1%) of the 166 patients who received immunotherapy and CRT, and 14 (28.0%) of them had a CPS of ≥10. The median follow-up time for these 50 patients was 16.2 months (range, 4.8-29.5 months). Thirty-two patients (64.0%) developed disease progression during this follow-up period and 16 patients (32.0%) were dead. There were no significant differences in OS (P = .304; both median OS not reached; Supplementary Fig. S2A) or PFS (P = .925; median PFS: 12.9 vs. 13.3 months; Supplementary Fig. S2B) for patients with PD-L1 <10 versus those with PD-L1 CPS ≥10.
Discussion
Based on a large cohort of patients with ESCC from an academic institution, our study found that the overall trends of ALC changes during CRT in ESCC patients who received definitive CRT with or without anti-PD-1 immunotherapy were similar. However, we found that ALC decreased less rapidly during radiotherapy and that the ALC nadir was higher in patients receiving ICIs. Of note, the addition of anti-PD-1 immunotherapy to definitive CRT could improve OS compared to traditional CRT, which may be explained in part by the attenuated decrease in ALC. Moreover, low ALC nadir during CRT was associated with worse survival, larger PTV, and higher heart V5 in the ICI group.
As an essential component of host immunity, lymphocytes play a central role in preventing tumor development and progression. The association between lymphopenia and poor prognosis has been demonstrated in a variety of solid tumors. With the promotion of immunotherapy, the function and role of lymphocytes in immunotherapy have received increasing attention. Ho et al found that patients with head and neck squamous carcinoma whose pre-treatment ALC<0.6 × 103 cells/μL had significantly worse responses to immunotherapy and shorter PFS.19 According to a study by Cho et al on non-small cell lung cancer patients treated with immunotherapy, treatment-related lymphopenia is a poor prognostic factor for survival.20 We reached a similar conclusion regarding ESCC patients, mainly that low ALC during definitive CRT suggested worse prognosis in patients treated with anti-PD-1 immunotherapy. Decreased ALC may lead to decreased efficacy of ICIs; reduced immune response to infection; and, ultimately, worse survival outcomes.
In previous studies of radiotherapy-associated lymphopenia in thoracic cancer treated with traditional CRT, ALC<0.2 × 103 cells/μL was often reported as the threshold value.15,17,18 However, the optimal cutoff value of ALC for patients who received CRT combined with immunotherapy remains unclear due to limited literature. In this study, ALC<0.33 × 103 cells/μL showed a good predictive effect for PFS. The higher cutoff value in our study may be the result of immunotherapy improving the lymphocyte status of patients during radiotherapy. However, it should be noted that the value of ALC<0.33 × 103 cells/μL has not been validated externally. Further studies are needed to prove the wide adaptability of this value or to define the optimal cutoff value of ALC in ESCC patients receiving immunotherapy to obtain a better balance between sensitivity and specificity.
Although several studies have investigated the role of lymphopenia in tumor response to ICIs, the effect of ICIs on lymphocytes has been rarely reported. We found that patients who received anti-PD-1 immunotherapy had less lymphocyte decrease during CRT than those who did not receive immunotherapy. This suggests that ICIs have a protective effect on lymphocytes, which may be another manifestation of the synergistic effect of radiotherapy and immunotherapy. Pembrolizumab increases the proliferation of peripheral blood T lymphocytes in melanoma patients after treatment.21 Yost et al found that the clonal expansion of tumor-infiltrating lymphocytes in response to anti-PD-1 immunotherapy was mainly from clones of T cells that were not detected in the tumor before treatment, while T cells previously present in the tumor did not expand after treatment.22 This suggests that anti-PD-1 immunotherapy promotes the proliferation of peripheral T cells and that proliferated T cells are recruited to play a role in the tumor microenvironment. This is likely because anti-PD-1 immunotherapy promotes the activation of T cells and the secretion of interferon-γ, tumor necrosis factor, and interleukin-2, which activates the host immune response and promotes increased release of immune cells from the bone marrow.23 Whether the improvement of ALC status in patients treated with anti-PD-1 immunotherapy is a direct cause or a correlate of the survival benefit is unclear, and the exact mechanism needs to be clarified.
Radiotherapy is a key factor in treatment-associated lymphopenia, but its mechanism remains to be studied. Radiation exposure affects the peripheral blood pool, while lymphocytes are highly radiosensitive. Moreover, radiotherapy can cause fibrosis in lymphoid organs such as bone marrow, thymus, spleen, and so on. Therefore, for radiotherapy-associated lymphopenia, the focus needs to be on the following 2 types of organs: organs with abundant blood circulation, such as the heart and lung, and organs that affect lymphocyte production and maturation, such as the thymus, lymph node, and bone marrow.24 For patients with thoracic malignancies, particular attention is required because heart, large blood vessels, and lung are usually included in the radiation field. By multivariate regression analysis, we found that PTV and heart V5 could predict low ALC during CRT in EC patients receiving ICI. Larger PTVs suggest larger radiation fields, including more lymphocytogenic sites and organs with high blood flow, leading to an increased incidence of lymphocytopenia. This is consistent with the results of previous studies.16,17 Although PTV is largely dependent on the size of the primary tumor, minimizing irradiation areas of uninvolved lymph nodes in clinical practice may reduce the risk of radiotherapy-associated lymphopenia. As heart of V5 is a modifiable parameter, we further determined heart V5 of 46% as an optimal cutoff value by using receiver operating characteristic curves. Although dosimetric parameters of the lungs in this study were not related to low ALC nadir in multivariate analyses, previous studies also indicated that lung DVH parameters such as V5 or V10 exhibited a significant association with lymphopenia.7,17 Because almost all circulating blood passes through the pulmonary circulation, the radiation dose received by the lungs reflects it is absorbed by circulating lymphocytes.16 Therefore, low-dose areas of the lung and heart should be minimized to mitigate lymphopenia. To our knowledge, this is the first study to assess the effect of dosimetric parameters on lymphopenia in EC patients treated with immunotherapy.
Based on this study and previous studies, lymphopenia is closely associated with poor prognosis in cancer patients. Together with the critical role of lymphocytes in antitumor therapy in the era of immunotherapy, it is important to explore strategies to correct or reduce lymphopenia. Cytokines have significant effects on lymphocyte development and function. The ELYPSE-7 study found that recombinant IL-7 (CYT107) induced remarkable increases in CD4+ and CD8+ T-cell counts in patients with metastatic breast cancer.25 Also, rhIL-7 was found to increase CD4+ T cells in idiopathic CD4 lymphocytopenia.26 In addition to IL-7, IL-15 has been reported to be safe for use in patients with metastatic malignancies and significantly increase NK cells and CD8+ memory T cells.27 Recently, thymosin-α1 was given to COVID-19 patients with severe lymphopenia to enhance immunity.28 Thymosin-α1 could increase T-cell account, promote T-cell maturation and restore thymic function.29 Hadden et al observed marked increases in CD45+/RA+ T cells (>250/mm3) after giving a mixture of thymosin-α1 and natural cytokine mixture to head and neck squamous cell carcinoma patients with lymphopenia.30 In addition, Campian et al demonstrated that pre-radiotherapy lymphocyte harvesting and post-radiotherapy reinfusion were safe and effective in patients with high-grade glioma.31 Taken together, these strategies showed promising preliminary results, but further prospective studies are needed to confirm their efficacy in the treatment of lymphopenia.
We also found that the addition of immunotherapy improved OS of ESCC patients who received definitive CRT. However, phase III randomized controlled clinical trials of CRT combined with immunotherapy are still ongoing.32,33 As reported in the PALACE-1 study, preoperative pembrolizumab in combination with concurrent CRT in locally advanced ESCC showed acceptable safety and promising antitumor activity.10 Recently, a phase II clinical trial evaluated the efficacy of durvalumab and tremelimumab in combination with definitive radiation in patients with unresectable locally advanced ESCC.34 The 24-month rates of PFS and OS were 57.5% and 75%, respectively, which were significantly better than the historical control group.34 The results of our study also support the promising efficacy of combined anti-PD-1 immunotherapy and CRT. Final results of phase III trials are still awaited to reveal the status of immunotherapy in combination with CRT in EC.32,33
Mechanistically, the PD-1 site of action is dependent on PD-L1 expression, making PD-L1 a biomarker worth investigating to predict the benefit of immunotherapy. Response to ICI was strongly correlated with PD-L1 status in several cancers.35 In advanced patients with esophageal cancer, the KEYNOTE-590 trial showed that patients with PD-L1 CPS ≥10 benefited the most from the combination of pembrolizumab and chemotherapy.5 Nevertheless, the JUPITER-06 study reported no obvious correlation between survival and PD-L1 expression in advanced ESCC.36 In our study, although OS seemed to be slightly better in the PD-L1 CPS ≥10 group than in the CPS <10 group, the difference was not statistically significant. The threshold of PD-L1 overexpression varies among studies, and multiple antibodies used in different studies may also affect the accurate assessment of PD-L1 expression. Therefore, further studies exploring the value of PD-L1 as a biomarker to predict the immunotherapy response in patients with ESCC is warranted.
The limitations of this study need to be mentioned. First, as a single-center retrospective study, a risk of selection bias cannot be excluded. Second, due to the lack of flow cytometry, we were unable to analyze the relationship between lymphocyte subtypes and clinical outcomes. In addition, there was heterogeneity of immunotherapy regimens in this study. Moreover, the cutoff value of ALC<0.33 × 103 cells/μL during CRT should be validated in future studies. Finally, owing to the relatively persistent effect of immunotherapy, patients who respond to immunotherapy usually showed better long-term OS.8 Therefore, the short follow-up time of this study limited the exploration of the relationship between lymphopenia and OS.
Conclusions
The addition of anti-PD-1 immunotherapy to definitive CRT could mitigate the decline of ALC during radiotherapy and might prolong survival. Low ALC nadir was correlated to worse PFS, larger PTV, and higher heart V5 in patients receiving combined immunotherapy and CRT. Future research should focus on the interaction between immunotherapy and radiation, optimizing radiotherapy regimens and immunotherapy strategies to protect lymphocytes and maximize the synergistic effects of radiotherapy and immunotherapy.
Supplementary Material
Acknowledgements
We would like to thank the patients who participated in this research.
Contributor Information
Xingyuan Cheng, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Baoqing Chen, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Sifen Wang, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Jun Zhang, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Jinhan Zhu, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Mengzhong Liu, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Shiliang Liu, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Mian Xi, State Key Laboratory of Oncology in South People’s Republic of China Collaborative Innovation Centre for Cancer Medicine, Guangdong Esophageal Cancer Institute, Guangzhou, People’s Republic of China; Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China.
Funding
This work was supported by grants from the National Natural Science Foundation of China (No. 82172669), the Sci-Tech Project Foundation of Guangzhou (202102080059), and the Guangdong Esophageal Cancer Institute Science and Technology Program (M202117).
Conflict of Interest
The authors indicated no financial relationships.
Author Contributions
Conception/design: S.L., M.X. Provision of study material or patients: B.C., S.L., M.L., M.X. Collection and/or assembly of data: X.C., S.W., J.Zhang, J.Zhu, M.X. Data analysis and interpretation: All authors. Manuscript writing: All authors. Final approval of manuscript: All authors.
Data Availability
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.